Donepezil is an acetyl cholinesterase inhibitor exhibiting high selectivity, high bioavailability, and high potency. It is able to inhibit acetyl cholinesterase present in the brain while only slightly effecting acetylcholine levels present in other tissues, such as the myocardium and the erythrocytes specifically. Other advantages of using Donepezil include its persistent activity and good safety profile. In addition, patients taking Donepezil have good tolerance for the drug. Since Donepezil demonstrated good efficacy in the treatment of Alzheimer senile dementia, it is a very valuable drug with growing market share. Accordingly, Donepezil and its derivatives is a hot synthetic target.
The synthesis of Donepezil was first disclosed by Japan's Eisai Co. in the U.S. Pat. No. 5,100,901 (see FIG. 1 herein), with an overall yield of less than 20%.
EPO Patent EP 535496 then disclosed an economically viable scheme for the synthesis of Donepezil (see FIG. 2 herein). However, this synthetic route resulted in many by-products in the first step, and required complicated purification procedures, such as column chromatography. We have found similar problems when we attempted to repeat this process. In addition, this process was difficult to reproduce. Therefore, it inevitably lead to complex purification procedure and a poor overall yield of 29 percent (see FIG. 2 herein). We predict that this process would be difficult to employ on an industrial scale. There are no continued patent applications of EP 535496 so far.
The German Company Bayer disclosed yet another process for the production of Donepezil in the U.S. Pat. No. 5,606,064 (see FIG. 3 herein). This process consists of 2 steps. The overall yield of this process is reported as 53%. However, when scientists of Eisai Co. attempted to repeat this process, they had found that the yield for the key step, step 2, was actually only 38% (U.S. Pat. No. 6,252,081). Therefore, the total yield of the Bayer process could not have been more than 27% overall.
Recently, Eisai Co. disclosed in the U.S. Pat. No. 6,252,081 an improved route for the preparation of Donepezil (see FIG. 4 herein). This route calls for recrystallization at each step, and the yield in the key step (last step) is high, while the by-products in that step are few. Hence, this route is the most efficient process at present, with a 69% overall yield. However, this route utilizes NaH in two steps, a high concentration NaOH solution in one step, and requires absolute dry solvents in two steps. As such, the route utilizes complicated operating parameters in each step, necessitating large investment for equipment, such as moisture proof equipment and caustic resistant equipment.
Finetech also developed two novel processes (U.S. Pat. No. 6,252,081; see FIGS. 5 and 6 herein). The yield of the process as illustrated in FIG. 5 was not disclosed, and the process required complicated purification techniques and column chromatography in many of its steps. Therefore, this process is not deemed suitable as an industrial process.
Although the synthesis, disclosed in FIG. 6 herein, requires multiple steps, it employs purification by recrystallization and distillation rather than by column chromatography in each step; this renders the industrialization of the process possible. It is said that the process was successfully employed in a pilot plant. However, this process also requires complicated operating parameters in each step, and utilizes strong acid and caustic reagents in multiple steps, generating a lot of waste. This process requires many complicated steps, and although the yields of each step are high, the overall yield was a mere 19.3% (see FIG. 6 herein). For these reasons, the commercial value of the process is limited.
In sum, there were 6 previously disclosed processes for the preparation of Donepezil and its derivatives. Wherein the process in FIG. 1 (herein) is an industrial one, processes in FIGS. 4 and 6 succeeded in a pilot plant. There is no continued patent application of the process in FIG. 6 (herein) after its EP application. There is also no successful report of a pilot plant of the process in FIG. 3 (herein).
The processes in FIGS. 2 and 3 have the shortest synthetic route. With respect to the results of the synthetic scheme illustrated herein in FIG. 2 which we have repeated, because the 2,3-dihydro-5,6-dimethoxy-2-((pyridin-4-yl)methylene)inden-1-one is a conjugated system, it is difficult to hydrogenate the pyridine ring and the carbon-carbon double bond at the same time in the presence of a catalyst. If hydrogenation is performed at an elevated temperature and pressure, the carbonyl group may also be reduced to a hydroxyl group making the purification more difficult, and yielding less than 40% of the desired material after purification by column chromatography. Moreover, the process illustrated herein in FIG. 3 also causes trouble in the same step of catalytic hydrogenation; although the N-benzylization on the pyridine ring can form a quaternary pyridinium salt, which makes the pyridine ring more active towards hydrogenation, the benzyl group is easily broken up by hydrogenolysis under these conditions as well. The results obtained by Eisai Co. and those obtained in our laboratory show that this reaction has many by-products, which makes the purification difficult, and the yields low.
There are two methods to solve the aforesaid problems, one is to use the synthetic scheme Eisai Co. developed as shown herein in FIG. 4: the pyridine analogues obtained from this process are not conjugated with the indanone ring; the pyridine ring can be activated through forming quaternary pyridinium salt; and as a result, the pyridine ring in the form of the N-benzyl quaternary pyridinium salt can be hydrogenated under mild reaction conditions. Consequently, the final products are obtained in higher yields.
The other method is to activate the pyridine ring by forming quaternary methyl ammonium salts rather than quaternary benzyl ammonium salts, and in this way to avoid the side reactions in the presence of a hydrogenation catalyst, as in the process disclosed by Joseph Sam (J. Hetercyclo. Chem. Vol. 2, 366; FIG. 7 herein). However, although the yield of this process is said to be 100%, this process is not suitable for the preparation of Donepezil.